Instructions for use Controloc gastro-resistant tablets 40 mg No. 14
Composition
active ingredient: pantoprazole;
1 tablet contains 45.1 mg of pantoprazole sodium sesquihydrate (equivalent to 40.0 mg of pantoprazole);
excipients: mannitol (E 421); sodium carbonate anhydrous; crospovidone; povidone K 90; calcium stearate;
shell: hypromellose 2910; povidone K 25; titanium dioxide (E 171); iron oxide yellow (E 172); propylene glycol; methacrylate copolymer (type A); sodium lauryl sulfate; polysorbate 80; triethyl citrate; brown ink (S-1-16350).
Dosage form
Gastro-resistant tablets.
Main physicochemical properties: yellow, oval, biconvex tablets, film-coated, with white or almost white cores, marked with brown ink on one side "P40".
Pharmacotherapeutic group
Drug for the treatment of acid-dependent diseases. Proton pump inhibitors. Pantoprazole. ATC code A02B C02.
Pharmacological properties
Pharmacodynamics
Mechanism of action: Pantoprazole is a substituted benzimidazole that inhibits gastric acid secretion by specific blockade of the proton pumps of parietal cells.
Pantoprazole is converted to its active form in the acidic environment of the parietal cells, where it inhibits the enzyme H+-K+-ATPase, i.e. blocks the final stage of hydrochloric acid production in the stomach. Inhibition is dose-dependent and affects both basal and stimulated acid secretion. In most patients, symptoms resolve within 2 weeks. The use of pantoprazole, like other proton pump inhibitors and H2-receptor inhibitors, reduces acidity in the stomach and, thus, increases gastrin secretion in proportion to the decrease in acidity. The increase in gastrin secretion is reversible. Since pantoprazole binds the enzyme distal to the cell receptor, it can inhibit hydrochloric acid secretion regardless of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same when the drug is administered orally and intravenously.
Pantoprazole increases fasting gastrin levels. In short-term use, they usually do not exceed the upper limit of normal. In long-term treatment, gastrin levels are usually doubled. Excessive increases occur only in isolated cases. As a result, a slight to moderate increase in specific endocrine (ECL) cells in the stomach (similar to adenomatoid hyperplasia) has sometimes been observed during long-term treatment. However, according to studies conducted to date, the formation of precursor cells for neuroendocrine tumors (atypical hyperplasia) or neuroendocrine tumors of the stomach, which have been observed in animal studies, has not been observed in humans.
Based on the results of animal studies, an effect of long-term (more than one year) treatment with pantoprazole on thyroid endocrine parameters cannot be completely excluded.
During treatment with antisecretory drugs, serum gastrin levels increase in response to decreased acid secretion. In addition, chromogranin A (CgA) levels increase due to decreased gastric acidity. Elevated CgA levels may interfere with diagnostic tests for neuroendocrine tumors. Available published data suggest that proton pump inhibitor treatment should be discontinued for 5 days to 2 weeks before CgA measurements. This allows CgA levels, which may be falsely elevated after PPI treatment, to return to the normal range.
Pharmacokinetics
Absorption. Pantoprazole is rapidly absorbed and peak plasma concentrations are reached after a single oral dose of 40 mg. Peak serum concentrations of approximately 2–3 μg/ml are reached on average 2.5 hours after administration; concentrations remain constant after multiple administration. The pharmacokinetic properties are not affected by single or repeated administration. In the dose range of 10 to 80 mg, the plasma pharmacokinetics of pantoprazole remain linear after both oral and intravenous administration. The absolute bioavailability of pantoprazole tablets has been shown to be approximately 77%. Concomitant food intake does not affect AUC (area under the concentration-time curve) or peak serum concentrations, and therefore bioavailability. Only the variability of the latent period increases with concomitant food intake.
Distribution: The binding of pantoprazole to serum proteins is about 98%. The volume of distribution is about 0.15 l/kg.
Biotransformation. The substance is metabolized almost exclusively in the liver. The main metabolic pathway is demethylation by CYP2C19 followed by sulfate conjugation; other metabolic pathways include oxidation by CYP3A4.
The main part of the metabolites of pantoprazole is excreted in the urine (about 80%), the rest is excreted in the feces. The main metabolite in both serum and urine is desmethylpantoprazole, conjugated with sulfate. The half-life of the main metabolite (about 1.5 hours) is slightly longer than that of pantoprazole.
Special patient groups.
Poor metabolisers. Approximately 3% of Europeans have a low functional activity of the CYP2C19 enzyme; they are called poor metabolisers. In these individuals, the metabolism of pantoprazole is probably mainly catalysed by the CYP3A4 enzyme. After a single dose of 40 mg pantoprazole, the mean area under the plasma concentration-time curve was approximately 6 times larger in poor metabolisers than in subjects with a functionally active CYP2C19 enzyme (extensive metabolisers). The mean peak plasma concentration was increased by approximately 60%. These findings do not affect the posology of pantoprazole.
Renal impairment. There are no recommendations for dose reduction when prescribing pantoprazole to patients with reduced renal function (including patients on dialysis). As in healthy volunteers, the elimination half-life of pantoprazole is short. Only very small amounts of pantoprazole are dialysable. Although the main metabolite has a moderately long half-life (2–3 hours), elimination is still rapid, so accumulation does not occur.
Hepatic impairment: Although in patients with cirrhosis (Child-Pugh class A and B) the half-life increases to 7–9 hours and the AUC increases 5–7-fold, the maximum serum concentration increases only slightly – 1.5-fold – compared to that in healthy volunteers.
Elderly patients: The slight increase in AUC and Cmax in elderly volunteers compared to younger volunteers is also not clinically relevant.
Children: After a single oral dose of 20 or 40 mg pantoprazole, AUC and Cmax in children aged 5 to 16 years were within the range of the corresponding values in adults. After a single intravenous administration of pantoprazole at doses of 0.8 or 1.6 mg/kg to children aged 2 to 16 years, there was no significant relationship between the clearance of pantoprazole and the patient's age or body weight. The AUC and volume of distribution were similar to those in adults.
Indication
Adults and children aged 12 and over.
- Reflux esophagitis.
Adults.
- Eradication of Helicobacter pylori (H. pylori) in patients with H. pylori-associated gastric and duodenal ulcers in combination with appropriate antibiotics.
- Duodenal ulcer.
- Stomach ulcer.
- Zollinger-Ellison syndrome and other hypersecretory pathological conditions.
Contraindication
Hypersensitivity to the active substance, benzimidazole derivatives and any component of the drug.
Interaction with other medicinal products and other types of interactions
Medicinal products whose absorption is pH-dependent: Due to the complete and long-term inhibition of hydrochloric acid secretion, pantoprazole may affect the absorption of medicinal products for which the pH of the gastric juice is an important factor in their bioavailability (e.g. some antifungals such as ketoconazole, itraconazole, posaconazole, or other medicinal products such as erlotinib).
HIV protease inhibitors: Concomitant use of pantoprazole with HIV protease inhibitors (such as atazanavir) whose absorption is dependent on intragastric pH is not recommended due to a significant reduction in their bioavailability (see section 4.4).
If concomitant use of HIV protease inhibitors with proton pump inhibitors cannot be avoided, close clinical monitoring (e.g. viral load) is recommended. The daily dose of pantoprazole should not exceed 20 mg. Dose adjustment of HIV protease inhibitors may be necessary.
Coumarin anticoagulants (phenprocoumon and warfarin).
Concomitant use of pantoprazole with warfarin or phenprocoumon did not affect the pharmacokinetics of warfarin, phenprocoumon or the INR (international normalized ratio). However, increases in INR and prolongation of prothrombin time have been reported in patients receiving concomitant PPIs and warfarin or phenprocoumon. Increases in INR and prolongation of prothrombin time may lead to pathological bleeding and even death. Therefore, monitoring of INR and prothrombin time is necessary in such concomitant use.
Methotrexate: Concomitant use of high doses of methotrexate (e.g. 300 mg) and proton pump inhibitors has been reported to increase blood levels of methotrexate in some patients. Patients receiving high doses of methotrexate, e.g. for cancer or psoriasis, are advised to temporarily discontinue pantoprazole treatment.
Interactions of pantoprazole with other drugs that are metabolized through the same enzyme system cannot be excluded.
The results of a number of studies on possible interactions indicate that pantoprazole does not affect the metabolism of active substances metabolized by CYP1A2 (e.g. caffeine, theophylline), CYP2C9 (e.g. piroxicam, diclofenac, naproxen), CYP2D6 (e.g. metoprolol), CYP2E1 (e.g. ethanol), and does not affect p-glycoprotein, which is associated with the absorption of digoxin.
No interactions with concomitantly administered antacids were identified.
A study of the interaction of pantoprazole with certain antibiotics (clarithromycin, metronidazole, amoxicillin) administered concomitantly has been conducted. No clinically significant interactions between these drugs have been identified.
Medicinal products that inhibit or induce CYP2C19. CYP2C19 inhibitors, such as fluvoxamine, may increase the systemic exposure of pantoprazole. A dose reduction should be considered in patients receiving long-term high-dose pantoprazole therapy and in patients with impaired liver function. Inducers of enzymes that affect CYP2C19 and CYP3A4, such as rifampicin and St. John's wort (Hypericum perforatum), may reduce the plasma concentration of PPIs that are metabolized by these enzyme systems.
Drug-Laboratory Test Interactions: False-positive results of some urine screening tests for tetrahydrocannabinol have been reported in patients taking pantoprazole. Alternative confirmatory testing methods should be considered to confirm positive results.
Application features
Hepatic impairment: Patients with severe hepatic impairment should have their liver enzymes monitored regularly, especially during long-term treatment. If liver enzymes increase, treatment should be discontinued (see section 4.2).
Combination therapy. During combination therapy, the instructions for medical use of the respective medicinal products must be followed.
Gastric malignancies. Symptomatic response to pantoprazole may mask the symptoms of gastric malignancies and delay their diagnosis. In the presence of alarming symptoms (e.g. significant weight loss, recurrent vomiting, dysphagia, haematemesis, anaemia, melena), as well as in the presence or suspicion of gastric ulcer, malignancy should be excluded.
If symptoms persist despite adequate treatment, further examination is necessary.
HIV protease inhibitors: Concomitant use of pantoprazole with HIV protease inhibitors (such as atazanavir) whose absorption is dependent on intragastric pH is not recommended due to a significant reduction in their bioavailability (see section 4.5).
Vitamin B12 absorption. In patients with Zollinger-Ellison syndrome and other hypersecretory pathological conditions requiring long-term treatment, pantoprazole, like all drugs that block the production of hydrochloric acid, may reduce the absorption of vitamin B12 (cyanocobalamin) due to the occurrence of hypo- and achlorhydria. This should be taken into account in patients with low body weight or the presence of risk factors for reduced absorption of vitamin B12 during long-term treatment, or in the presence of relevant clinical symptoms.
Long-term treatment. With long-term treatment, especially more than 1 year, patients should be under regular medical supervision.
Gastrointestinal infections caused by bacteria. Treatment with Controloc® may slightly increase the risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter or C. Difficile.
Hypomagnesemia: Rare cases of severe hypomagnesemia have been reported in patients receiving proton pump inhibitors (PPIs) such as pantoprazole for at least three months, and in most cases for a year. Serious clinical manifestations of hypomagnesemia may occur and may initially be insidious: fatigue, tetany, delirium, convulsions, dizziness and ventricular arrhythmias. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia (see section 4.8). In the case of hypomagnesemia (and hypocalcemia and/or hypokalemia associated with hypomagnesemia), in most cases the patient's condition improved after magnesium replacement therapy and discontinuation of the PPI.
Bone fractures. Long-term treatment (more than 1 year) with high doses of proton pump inhibitors may modestly increase the risk of hip, wrist, and spine fractures, predominantly in elderly patients or in those with other risk factors. Observational studies suggest that proton pump inhibitor use may increase the overall risk of fractures by 10–40%. Some of these may be due to other risk factors. Patients at risk of osteoporosis should be treated according to current clinical guidelines and consume adequate amounts of vitamin D and calcium.
Severe cutaneous adverse reactions. Severe cutaneous adverse reactions of unknown frequency (see section 4.8) that can be life-threatening or fatal, such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported with pantoprazole. Patients should be informed of the signs and symptoms of the above-mentioned cutaneous reactions and should be closely monitored for their development. If signs and symptoms suggestive of these reactions occur, pantoprazole should be discontinued immediately and alternative treatment should be considered.
Subacute cutaneous lupus erythematosus. The use of proton pump inhibitors has been associated with very rare cases of subacute cutaneous lupus erythematosus. If lesions occur, especially in areas exposed to sunlight, and are accompanied by arthralgia, the patient should immediately consult a doctor who will consider discontinuing Controloc®. The occurrence of subacute cutaneous lupus erythematosus in patients during previous therapy with proton pump inhibitors may increase the risk of its development with the use of other proton pump inhibitors.
Impact on laboratory test results.
Elevated levels of chromogranin A (CgA) may interfere with the results of tests used to diagnose neuroendocrine tumors. To avoid this interference, treatment with Controloc® should be temporarily discontinued for at least 5 days before CgA measurements are performed (see section 5.2). If CgA and gastrin levels have not returned to the normal range after initial measurement, repeat measurements should be performed 14 days after discontinuation of proton pump inhibitor treatment.
Sodium. Controloc® contains less than 1 mmol sodium (23 mg) per tablet, i.e. essentially sodium-free.
Use during pregnancy or breastfeeding
Pregnancy: Available data on the use of pantoprazole in pregnant women (approximately 300-1000 pregnancy outcomes) indicate no embryonal or foeto/neonatal toxicity of pantoprazole. Reproductive toxicity has been observed in animal studies. As a precautionary measure, the use of Controloc® should be avoided in pregnant women.
Breastfeeding. Animal studies have shown excretion of pantoprazole in breast milk. There is insufficient data on the excretion of pantoprazole in human milk, but such excretion has been reported. A risk to the newborn/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Controloc therapy taking into account the benefit of breast-feeding for the child and the benefit of Controloc therapy for the woman.
Fertility: Pantoprazole did not impair fertility in animal studies.
Ability to influence reaction speed when driving vehicles or other mechanisms
Pantoprazole has no or very minor influence on the ability to drive or use machines. It is necessary to take into account the possible development of side effects such as dizziness and visual disturbances (see section "Adverse reactions"). In such cases, you should not drive or use machines.
Method of administration and doses
Controloc®, gastro-resistant tablets, should be taken 1 hour before meals whole, do not chew or crush, and should be washed down with water.
Recommended dosage.
Adults and children aged 12 and over.
Treatment of reflux esophagitis.
The recommended dose is 1 tablet of Controloc® 40 mg per day. In some cases, the dose can be doubled (2 tablets of Controloc® 40 mg per day), especially if other drugs for the treatment of reflux esophagitis are ineffective. Reflux esophagitis usually takes 4 weeks to treat. If this is not enough, healing can be expected within a further 4 weeks.
Adults.
Eradication of H. pylori in combination with two antibiotics.
In adult patients with gastric and duodenal ulcers and positive for H. pylori, eradication of the organism should be achieved using combination therapy. Local data on bacterial resistance and national guidelines for the use and prescription of appropriate antibacterial agents should be taken into account. Depending on susceptibility, the following therapeutic combinations may be prescribed for the eradication of H. pylori in adults:
+ 1000 mg of amoxicillin 2 times a day
+ 500 mg of clarithromycin 2 times a day;
b) 1 tablet of Controloc® 40 mg 2 times a day
+ 400–500 mg metronidazole (or 500 mg tinidazole) 2 times a day
+ 250–500 mg of clarithromycin 2 times a day;
c) 1 tablet of Controloc® 40 mg 2 times a day
+ 1000 mg of amoxicillin 2 times a day
+ 400–500 mg of metronidazole (or 500 mg of tinidazole) 2 times a day.
When using combination therapy for the eradication of H. pylori, the second tablet of Controloc® 40 mg should be taken in the evening 1 hour before a meal. The duration of treatment is 7 days and can be extended for another 7 days. The total duration of treatment is no more than two weeks. If further treatment with pantoprazole is indicated to ensure ulcer healing, the dosage recommendations for gastric and duodenal ulcers should be considered. If combination therapy is not indicated, for example, in patients with a negative result for H. pylori, Controloc® 40 mg is used for monotherapy in the dosage indicated below.
Treatment of stomach ulcers.
1 tablet of Controloc® 40 mg per day. In some cases, the dose can be doubled (2 tablets of Controloc® 40 mg per day), especially if there is no effect from the use of other drugs.
It usually takes 4 weeks to heal a stomach ulcer. If this is not enough, healing of the ulcer can be expected within another 4 weeks.
Treatment of duodenal ulcers.
1 tablet of Controloc® 40 mg per day. In some cases, the dose can be doubled (2 tablets of Controloc® 40 mg per day), especially if there is no effect from the use of other drugs.
Duodenal ulcers usually take 2 weeks to heal. If this is not enough, healing of the ulcer can be expected within another 2 weeks.
Treatment of Zollinger-Ellison syndrome and other hypersecretory pathological conditions.
For long-term treatment of Zollinger-Ellison syndrome and other pathological hypersecretory conditions, the initial daily dose is 80 mg (2 tablets of Controloc® 40 mg). If necessary, the dose can then be titrated up or down, depending on the acidity of the gastric juice. A dose exceeding 80 mg per day should be divided into two doses. A temporary increase in the dose to more than 160 mg of pantoprazole is possible, but the duration of use should be limited only to the period necessary for adequate acidity control.
The duration of treatment for Zollinger-Ellison syndrome and other pathological conditions is not limited and depends on clinical need.
Patients with hepatic impairment. Patients with severe hepatic impairment should not exceed a daily dose of 20 mg (1 tablet of Controloc® 20 mg). Controloc® should not be used for the eradication of H. pylori in combination therapy in patients with moderate to severe hepatic impairment, as there is currently no data on the efficacy and safety of such use in this category of patients.
Patients with renal impairment. No dose adjustment is required for patients with renal impairment. Controloc® should not be used for H. pylori eradication in combination therapy in patients with renal impairment, as there is currently no data on the efficacy and safety of such use in this category of patients.
Elderly patients do not require dose adjustment.
Children. Controloc® 40 mg is indicated in children aged 12 years and older for the treatment of reflux esophagitis. The drug is not recommended for use in children under 12 years of age, as data on safety and efficacy in this age group are limited.
Overdose
Symptoms of overdose are unknown.
Doses up to 240 mg administered intravenously over 2 minutes have been well tolerated. Since pantoprazole is extensively protein bound, it is not readily dialyzable.
In case of overdose with clinical signs of intoxication, symptomatic and supportive therapy is used. There are no specific therapy recommendations.
Adverse reactions
The occurrence of adverse reactions was observed in about 5% of patients.
Adverse effects are classified by frequency of occurrence into the following categories: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10000 and < 1/1000), very rare (< 1/10000), unknown (frequency not determined based on available data).
For all adverse reactions reported during the post-marketing period, it is not possible to determine the frequency and are therefore indicated as “not known”.
Within each frequency category, adverse reactions are presented in order of decreasing seriousness.
From the blood and lymphatic system.
Rare: agranulocytosis.
Very rare: leukopenia, thrombocytopenia, pancytopenia.
From the immune system.
Rare: hypersensitivity reactions (including anaphylactic reactions, anaphylactic shock).
Metabolism and metabolic disorders.
Rare: hyperlipidemia and increased lipid levels (triglycerides, cholesterol), changes in body weight.
Not known: hyponatremia, hypomagnesemia (see section 4.4), hypocalcemia1, hypokalemia1.
Mental disorders.
Uncommon: sleep disorders.
Rare: depression (including exacerbation).
Not known: hallucination, confusion (especially in patients with a predisposition to such disorders, as well as exacerbation of these symptoms in case of pre-existing conditions).
From the nervous system.
Uncommon: headache, dizziness.
Rare: taste disorders.
Not known: paraesthesia.
From the organ of vision.
Rare: visual disturbances/blurred vision.
From the digestive tract.
Common: fundic gland polyps (benign).
Uncommon: diarrhoea, nausea, vomiting, abdominal bloating, constipation, dry mouth, abdominal pain and discomfort.
Not known: microscopic colitis.
On the part of the hepatobiliary system.
Uncommon: increased liver enzymes (transaminases, g-GT).
Rare: increased bilirubin levels.
Not known: hepatocyte damage, jaundice, hepatocellular failure.
On the skin and subcutaneous tissue.
Uncommon: skin rash, exanthema, pruritus.
Rare: urticaria, angioedema.
Not known: Stevens-Johnson syndrome, Lyell's syndrome (toxic epidermal necrolysis), drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme, photosensitivity, subacute cutaneous lupus erythematosus (see section "Special warnings and precautions for use").
On the part of the musculoskeletal system and connective tissue.
Uncommon: fractures of the hip, wrist, spine (see section "Special warnings and precautions for use").
Rare: arthralgia, myalgia.
Not known: muscle spasm2.
On the part of the kidneys and urinary system.
Not known: tubulointerstitial nephritis (with possible development of renal failure).
From the reproductive system and mammary glands.
Rare: gynecomastia.
General disorders.
Uncommon: asthenia, fatigue, malaise.
Rare: fever, peripheral edema.
1 Hypocalcemia and/or hypokalemia may be associated with the development of hypomagnesemia (see section "Special warnings and precautions for use").
2 Muscle spasm as a result of electrolyte imbalance.
Reporting of suspected adverse reactions
Reporting of adverse reactions after registration of a medicinal product is important. This allows monitoring of the benefit/risk ratio of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the automated pharmacovigilance information system (https://aisf.dec.gov.ua).
Expiration date
3 years.
Storage conditions
Does not require special storage conditions. Keep out of the reach of children!
Packaging
14 tablets in a blister; 1 or 2 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
Takeda GmbH, production site Oranienburg, Germany / Takeda GmbH Betriebsstätte Oranienburg, Germany.
Location of the manufacturer and its address of business. Lehnitzstrasse 70-98, 16515, Oranienburg, Germany.
